Algorithm for the automatic determination of optimal pacing intervals

ABSTRACT

Impedance, e.g. sub-threshold impedance, is measured across the heart at selected cardiac cycle times as a measure of chamber expansion or contraction. One embodiment measures impedance over a long AV interval to obtain the minimum impedance, indicative of maximum ventricular expansion, in order to set the AV interval. Another embodiment measures impedance change over a cycle and varies the AV pace interval in a binary search to converge on the AV interval causing maximum impedance change indicative of maximum ventricular output. Another method varies the right ventricle to left ventricle (VV) interval to converge on an impedance maximum indicative of minimum cardiac volume at end systole. Another embodiment varies the VV interval to maximize impedance change. Other methods vary the AA interval to maximize impedance change over the entire cardiac cycle or during the atrial cycle.

FIELD OF THE INVENTION

The present invention is related generally to implantable cardiacpacemakers and cardioverter defibrillators. More specifically, thepresent invention includes apparatus and methods for using impedancemeasurements to set optimal pacing intervals.

BACKGROUND OF THE INVENTION

Congestive heart failure (CHF) is defined generally as the inability ofthe heart to deliver enough blood to the peripheral tissues to meetmetabolic demands. Frequently CHF is associated with left heartdysfunction, but it can have a variety of other causes. For example, CHFpatients may have any one of several different conduction defects. Thenatural electrical activation system through the heart involvessequential events starting with the sino-atrial (SA) node, andcontinuing through the preferred conduction pathways at the atriallevel, followed by the atrio-ventricular (AV) node, Common Bundle ofHis, right and left bundle branches, and final distribution to thedistal myocardial terminals via the Purkinje fiber network. A commontype of intra-atrial conduction defect is known as intra-atrial block(IAB), a condition where the atrial activation is delayed in gettingfrom the right atrium to the left atrium. In left bundle branch blockand right bundle branch block, the activation signals are not conductedin a normal fashion along the left or right bundle branchesrespectively. Thus, in a patient with bundle branch block, theactivation of the ventricle is slowed, and the QRS is seen to widen dueto the increased time for the activation to traverse the conductionpath.

CHF resulting from such conduction defects and/or other cardiomyopathiesare the object of considerable research. It is known generally thatfour-chamber cardiac pacing and atrial synchronous bi-ventricular pacingcan provide significant improvement for patients having atrial orventricular mechanical dysynchrony resulting in dysfunction and symptomsof congestive heart failure.

The benefits of four-chamber pacing and atrial synchronousbi-ventricular pacing generally have been disclosed and published in theliterature. Cazeau et al., PACE, Vol. 17, November.1994, Part II, pp.1974-1979, disclosed investigations leading to the conclusion thatfour-chamber pacing was feasible, and that in patients with evidence ofinterventricular dysynchrony, a better mechanical activation process canbe obtained by resynchronizing depolarization of the right and leftventricles, and optimizing the AV sequence on both sides of the heart.In the patent literature, U.S. Pat. No. 4,928,688 is representative of asystem for simultaneous left ventricular (LV) and right ventricular (RV)pacing; natural ventricular depolarizations are sensed in both chambers,if one chamber contracts but the other one does not within a window ofup to 5-10 ms, then the non-contracting ventricular chamber is paced.

Further, similar to the advantages of substantially simultaneous orsynchronous pacing of the two ventricles, there is an advantage tosynchronous pacing of the left atrium and the right atrium for patientswith IAB (inter-atrial block). In a normal heart, atrial activationinitiates with the SA node. In a patient with IAB, the activation isslow being transferred over to the left atrium, and as a result the leftatrium may be triggered to contract up to 90 ms later than the rightatrium. It can be seen that if contractions in the left ventricle andthe right ventricle are about the same time, then left AV synchrony isway off, with the left ventricle not having adequate time to fill up.The advantage of synchronous pacing of the two atria for patients withIAB is disclosed at AHA 1991, Abstract from 64th Scientific Sessions,“Simultaneous Dual Atrium Pacing in High Degree Inter-Atrial Blocks:Hemodynamic Results,” Daubert et al., No. 1804

Further, it is known that patients with IAB are susceptible toretrograde activation of the left atrium, with resulting atrialtachycardia. Atrial resynchronization through pacing of the atria can beeffective in treating the situation. PACE, Vol. 14, April 1991, Part II,p. 648, “Prevention of Atrial Tachyarrhythmias Related to Inter-AtrialBlock By Permanent Atrial Resynchronization,” Mabo et al., No. 122. Forpatients with this condition, a criterion for pacing is to deliver aleft atrial stimulus before the natural depolarization arrives in theleft atrium.

In view of the published literature, it is observed that in CHF patientsimproved pump function can be achieved by increasing the filling time ofthe left ventricle, i.e., improving the left AV delay, and specificallythe left heart mechanical AV delay (MAVD); decreasing mitral valveregurgitation, (back flow of blood into the atrium through the nearlyclosed valve) by triggering contraction of the left ventricle when it ismaximally filled. More specifically, for a cardiac pacing system usedfor treating a CHF patient, the aim is to synchronize atrial andventricular contractions through optimization of the left and right AVdelays so as to properly fill the ventricles and provide maximalfilling; and to activate the left ventricle as much as possible tocontract in synchrony with the right ventricle. Correct programming ofthe AV interval is key for optimizing the filling of the ventricles, andoptimizing ejection fraction, or cardiac output (CO). Particularly, theAV delay should be set to produce maximal filling of both ventriclesduring diastole and maximal emptying during systole.

Exact timing of left and right ventricular contraction is important forproperly controlling pacing so as to optimize left ventricular output.Specifically, it is known that actual contraction of one ventricularchamber before the other has the effect of moving the septum so as toimpair full contraction in the later activated chamber. Thus, whileconcurrent or simultaneous pacing of the left and right ventricle mayachieve a significant improvement for CHF patients, pacing both left andright ventricles at the same time may not always be optimal. Forexample, if conduction paths in the left ventricle are impaired,delivering a pacing stimulus to the left ventricle at precisely the sametime as to the right ventricle may nonetheless result in leftventricular contraction being slightly delayed with respect to the rightventricular contraction. Electrodes are now being positioned adjacentthe left ventricle, and can be activated with sequential or simultaneoustiming with respect to the right ventricle, resulting in varied timingand activation patterns. If the right and left ventricle are pacedsimultaneously this may not result in maximized pumping action, with theoptimal pacing lead or lag between the ventricles being patientspecific.

Echocardiography is sometimes used to set the AV interval in pacingdevices. In this procedure, ultrasound is used to produce an echocardiogram, followed by observation of the E and A waves. The AVinterval can be clinically varied to optimize the E and A waves, so thatthe atrium is allowed to contract and fill the ventricles before theventricle contracts. If the AV interval is too long, the valves areclosed at ventricular contraction. If the AV interval is too short, LVfilling does not receive the benefit of the atrial kick.Echocardiography is quite expensive, and can only be done infrequently,in a clinical setting. Quite frequently, the AV pacing intervals are setto a nominal AV interval, without echocardiography.

It is known to use impedance sensors in pacing systems, for obtaininginformation concerning cardiac function. For example, reference is madeto U.S. Pat. No. 5,501,702, incorporated herein by reference, whichdiscloses making impedance measurements from different electrodecombinations. In such system, a plurality of pace/sense electrodes aredisposed at respective locations, and different impedance measurementsare made on a time/multiplexing basis. As set forth in the referencedpatent, the measurement of the impedance present between two or moresensing locations is referred to “rheography.” A rheographic, orimpedance measurement involves delivering a constant current pulsebetween two “source” electrodes, such that the current is conductedthrough some region of the patient's tissue, and then measuring thevoltage differential between two “recording” electrodes to determine theimpedance therebetween, the voltage differential arising from theconduction of the current pulse through the tissue or fluid between thetwo recording electrodes. The referenced patent discloses usingrheography for measuring changes in the patient's thoracic cavity;respiration rate; pre-ejection interval; stroke volume; and heart tissuecontractility. It is also known to use this technique of four pointimpedance measurements, applied thoracically, for measuring smallimpedance changes during the cardiac cycle, and extracting the firsttime derivative of the impedance change, dZ/dt. It has been found that asubstantially linear relation exists between peak dZ/dt and peak cardiacejection rate, providing the basis for obtaining a measure of cardiacoutput. See also U.S. Pat. No. 4,303,075, disclosing a system formeasuring impedance between a pair of electrodes connected to or inproximity with the heart, and processing the variations of sensedimpedance to develop a measure of stroke volume. The AV delay is thenadjusted in an effort to maximize the stroke volume.

Given the demonstrated desirability of cardiac resynchronization therapy(CRT), or bi-ventricular pacing, and the availability of techniques forsensing natural cardiac signals and mechanical events, there nonethelessremains a need to provide pacing intervals which are tuned for improvingcardiac output, and in particular for improving left heart function.What would be particularly desirable is a method for also determiningthe optimal right side to left side pacing delay between the ventriclesto obtain maximum cardiac output.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods and devices for determiningoptimal atrial to ventricular (AV) pacing intervals and ventricular toventricular (VV) delay intervals in order to optimize cardiac output.Impedance, preferably sub-threshold impedance, is measured across theheart at selected cardiac cycle times as a measure of chamber expansionor contraction. The present methods can be used to particular advantagein four chamber and atrial synchronous bi-ventricular pacing devicesused in cardiac resynchronization therapy (CRT). The methods can beimplemented as executable logic or programs residing in implantedcardiac pacing devices.

A first method according to the present invention measures impedanceover a long AV interval to obtain the minimum impedance, indicative ofmaximum ventricular expansion, in order to set the AV interval. The AVinterval, as described in the present application, may extend fromeither A-sense or A-pace, with the term “A-event” being used to refer toeither A-pace or A-sense. The AV interval, A-event to V-pace or V-sense,can first be set to a longer than normal interval in a clinical setting.In one method, the AV interval is set to about 300 ms in order to obtaina long period for impedance data gathering over one cycle. The impedancecan be measured at multiple time points over the AV interval and thetime point of minimum impedance determined. The minimum impedance isbelieved to correspond to the point of maximum expansion and filling ofthe ventricle, an optimal time for ventricle contraction for achievingmaximum output. The time of impedance minimum can be used to set the AVpacing interval. Some methods reduce the time of minimum impedance by anoffset to account for cardiac electromechanical delays. In some methods,the time of minimum impedance can be determined for several cycles andaveraged. In yet another method, the impedance waveforms from severalbeats could be averaged together, after being aligned in time on theatrial or ventricular pacing pulse or sense, and the time of the minimumimpedance determined from the averaged waveform.

A second method according to the present invention measures impedancechange taken between times near the A-event and near the V-pace. Theimpedance change from A-event to V-pace is an impedance decrease as theventricle fills with conductive blood. This method attempts to maximizethe atrial contribution to ventricular filling by producing the largestabsolute change in volume (delta Z) between the A-event and V-pace,through manipulation of the AV interval. The impedance data can beobtained from measurements taken shortly after the A-pace and near theV-pace. The AV interval can be varied in a binary search to converge onmaximum impedance change indicative of maximum ventricular output. Insome methods, only one or a small number of impedance measurements aretaken after the A-pace, and shortly before, during, or shortly after theV-pace. The impedance change can be determined by subtracting theimpedance taken near the V-pace from the impedance taken near theA-pace. The small number of carefully timed measurements cansubstantially reduce the power required to determine the impedancechange.

In one method, a single impedance measurement is taken shortly afterA-event and a single measurement taken near the V-pace. In some methods,the impedance change is measured for several heart beats at the same AVinterval, and the average maximum impedance change over severalheartbeats used. In yet another method, the impedance waveforms fromseveral beats are averaged together, after being aligned on the atrialor ventricular pacing pulse or sense, and the maximum impedance changedetermined from the averaged waveform. The impedance change fromventricular expansion after atrial contraction can be maximized as afunction of AV interval to maximize the atrial contribution toventricular filling. The AV interval can be varied to bracket to maximumimpedance change over several beats. In one method, a search algorithmis used to rapidly converge on the maximum impedance change from bothtime directions. In a preferred method, a binary search is used toconverge on the maximum impedance change. The binary search can providerapid convergence in few heart beats requiring little power consumption.

A third method according to the present invention measures impedancechange taken between times shortly before, during, or shortly after thefirst V-pace until shortly before, during, or shortly after the nextA-event. This measurement range will identify the cardiac cycleimpedance maximum and minimum. This method attempts to maximize thechange in ventricular volume and largest change in impedance byproducing the greatest ventricular filling and maximal ventricularemptying over the ventricular ejection period through manipulation ofthe AV interval. The AV interval can be varied in a binary search toconverge on maximum impedance change indicative of maximum ventricularoutput. In some methods, only one or a small number of impedancemeasurements are taken shortly before, during, or shortly after thefirst V-pace, with the V-pace measurement being used in place of theminimum impedance to calculate the impedance change for a cardiac cycle.The impedance near the V-pace is typically very low, if not the minimum,and can be used to eliminate finding the minimum. The impedance changecan be determined by subtracting either the impedance taken near theV-pace, or the minimum impedance found, from the maximum impedance foundbetween the V-pace and the A-event.

In some methods, the impedance change is measured for several heartbeats at the same AV interval, and the average maximum impedance changeover several heartbeats used. In yet another method, the impedancewaveforms from several beats are averaged together, after being alignedon the atrial or ventricular pacing pulse or sense, and the maximumimpedance change determined from the averaged waveform. The impedancechange from expansion to contraction can be maximized as a function ofAV interval to maximize the cardiac output. The AV interval can bevaried to bracket the maximum impedance change over several beats. Inone method, a search algorithm is used to rapidly converge on themaximum impedance change from both time directions. In a preferredmethod, a binary search is used to converge on the maximum impedancechange. The binary search can provide rapid convergence in few heartbeats requiring little power consumption.

A fourth method varies the right ventricle to left ventricle (VV)interval to converge on an impedance maximum indicative of minimumcardiac volume at end systole. This method attempts to maximize thechange in ventricular volume and largest change in impedance byproducing the greatest ventricular filling and maximal ventricularemptying over the ventricular ejection period through manipulation ofthe VV interval. The maximum impedance in a cycle is obtained as anindication of the minimum cardiac volume associated with end systole.The impedance measurements can be taken at multiple times after V-paceuntil next A-pace. The time difference between pacing the right and leftventricle, the ventricle to ventricle (VV) interval, can be varied tofind the VV interval having the maximum impedance. The paced VV intervalcan be varied to bracket the maximum impedance over several heart beats.In one method, a search algorithm is used to rapidly converge on thepaced VV interval having the maximum impedance. In a preferred method, abinary search is used to converge on the paced VV interval having themaximum impedance change. The binary search can provide rapidconvergence in few heart beats. In some methods, the maximum impedanceis measured for several heart beats at the same VV interval, and theaverage maximum impedance over several heartbeats used. In yet anothermethod, the impedance waveforms from several beats is averaged togetherafter being aligned on the atrial or ventricular pacing pulse or sense,and the maximum impedance determined from the averaged waveform.

A fifth method varies the VV interval to maximize impedance change. Themaximum impedance change in a cycle is obtained as an indication of themaximum ventricular output. The impedance data can be obtained frommeasurements taken shortly after the V-pace until the next A-event. Thetime difference between pacing the right and left ventricle, or theventricle to ventricle (VV) interval, can be varied to find the VVinterval causing the maximum impedance change. The paced VV interval canbe varied to bracket the VV interval causing the maximum impedancechange. In one method, a search algorithm is used to rapidly converge onthe paced VV interval having the maximum impedance change. In apreferred method, a binary search is used to converge on the paced VVinterval having the maximum impedance change. In some methods, theimpedance change is measured for several heart beats at the same VVinterval, and the average maximum impedance change over severalheartbeats used. In yet another method, the impedance waveforms fromseveral beats are averaged together after being aligned on the atrial orventricular pacing pulse or sense, and the maximum impedance changedetermined from the averaged waveform.

In some combined methods, the AV interval is optimized using one of theAV interval optimization methods according to the present invention.With the AV interval set, the VV interval can be optimized using one ofthe present invention methods. The pacing device can then be set to paceusing the VV interval, causing the A-event to RV-pace and A-event toLV-pace interval to be either the same, lead, or lag each other. Withthe VV interval set, the AV interval can be re-optimized, this timeusing the just determined optimal VV interval.

Impedance measurements can be taken from pacing signals, but arepreferably measured using sub-threshold stimulation signals. In somemethods, the sub-threshold stimulation signals are stimulated RightVentricular Ring to Left Ventricular Ring, and measured RightVentricular Tip to Left Ventricular Tip. The impedance vector ispreferably selected to cross the left and/or right ventricle, dependingon the embodiment and available electrodes. Any suitable combination ofstimulation and sensing electrodes may be used in obtaining theimpedance measurement for use in the present invention.

The impedance measurement is often significantly changed by breathing.Impedance is effected greatly by electrode distance. Breathing changesthe dimensions of the chest and the position of the heart. The impedancemeasurement is thus usually a composite impedance formed of a smallamplitude, high frequency cardiac wave superimposed on a largeamplitude, low frequency breathing wave. Several methods can be used toprovide the AV and VV interval optimization methods with impedance databy taking into account the breathing impedance change contribution tothe composite impedance signal.

In one method, a patient assumes a supine position in a clinicalsetting, stops moving, and is instructed to hold their breath by aphysician. The patient has an implanted pacing unit implementing one ormore methods of the present invention. Upon breath hold, the physicianuses a programmer unit to signal the pacing device to measure impedance,preferably for a limited number of seconds or beats. The impedance maybe effected by breath hold, but at a constant level. The pacing unit canthen use the impedance data obtained to optimize an AV and/or VVinterval.

In another method, the patient assumes a supine position, stops moving,and holds their breath. The implanted pacing device detects thecombination of lack of movement (acceleration), and breath hold, andmeasures impedance for a period.

In still another method, preferably during a period of little movement,most preferably during sleep, the pacing device tracks the breathingcycle, through any means appropriate, including an impedance signal oraccelerometer signal. Logic executing in the implanted device can timeor “gate” the taking of impedance data to occur only near theinspiration peak or expiration nadir, preferably during the expirationnadir. Taking the impedance during these time regions, windows, orranges of relatively little impedance change can effectively eliminatemost of the impedance change due to breathing. In some embodiments, onlyone or two cardiac cycles per breath are measured for impedance.

In still another method, signal processing or filtering is used toremove the higher frequency, smaller amplitude cardiac impedance wavefrom the lower frequency, larger amplitude breathing wave. This methodis preferably done during sleep, during periods of little movement andregular breathing.

In one method, the AA interval is optimized according to a maximumimpedance change measured over an entire cardiac cycle. In anothermethod, the AA interval is optimized according to a maximum impedance ormaximum impedance change measured during the atrial cycle andcorresponding to maximum atrial ejection.

Methods used in obtaining impedance measurements for use by pacinginterval optimization methods may be implemented in an externalprogramming unit or in an implantable device. A programming unit mayprompt a physician to direct a patient in establishing one or moremeasurement conditions suitable for performing impedance measurementsfor optimizing AA, AV and/or VV intervals. An implanted medical devicemay detect the presence of one or more measurement conditions based onsensed physiological signals and then initiate impedance measurementsautomatically. A measurement condition may include one or moreparameters such as heart rate, posture, respiration, and activity level.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a system in accordance with thisinvention, whereby four bipolar leads are provided, the leads beingshown carrying bipolar electrodes positioned in each of the respectivecardiac chambers;

FIG. 2A is a block diagram of a four channel pacing system in accordancewith this invention, for pacing and sensing in each ventricle, and forobtaining impedance signals from the left heart and the right heart.

FIG. 2B is a schematic representation of an arrangement in accordancewith this invention for detecting left ventricular impedance fordetermination of cardiac output.

FIG. 3 is a block diagram of a four-chamber pacemaker with the abilityto time multiplex impedance measurements, in accordance with thisinvention.

FIG. 4 is a flow chart of a method for determining an optimal AVinterval by maintaining a long AV interval and searching for a timepoint within the interval having a minimum impedance corresponding to amaximally filled ventricle.

FIG. 5A is a flow chart of a method for obtaining an optimum AV intervalby intelligently varying the AV interval to search for the AV intervalcausing a maximum impedance change, measured from an A-event to aV-pace, corresponding to a maximum diastolic ventricular filling.

FIG. 5B is a flow chart of a method for obtaining an optimum AV intervalby intelligently varying the AV interval to search for the AV intervalcausing a maximum impedance change measured between a cardiac cycleminimum and a cardiac cycle maximum impedance located between V-pace andthe next A-event, corresponding to a maximum cardiac output.

FIG. 6 is a flowchart of a method for obtaining an optimalinter-ventricular time delay by intelligently varying theinter-ventricular time delay and searching for a maximum impedancecorresponding to a maximum contraction of the ventricles.

FIG. 7 is a flowchart of a method for optimizing the inter-ventriculardelay by intelligently varying the inter-ventricular delay and searchingfor the delay having a maximum impedance change corresponding to amaximum cardiac output.

FIG. 8 is a flow chart of a method for obtaining cardiac impedance datain clinical setting using breath holding as directed by a physician.

FIG. 9 is a flowchart of a method for obtaining impedance data in aclinical setting during a sensed breath hold.

FIG. 10 is a flowchart of a method for obtaining impedance data byremoving the slower frequency breathing contribution from the compositeimpedance signal.

FIG. 11 is a flowchart of a method for obtaining impedance data during avoluntary sensed breath hold.

FIG. 12 is a flowchart of a method for obtaining impedance data bygating, selecting impedance data during a sensed region with minimalrespiration changes.

FIG. 13 is a flowchart of a method for optimizing AV interval, then VVinterval, then re-optimizing the AV interval using the VV interval;

FIG. 14 is a flow chart of a general method for searching for timeshaving optimal impedance values or changes.

FIG. 15 is a flow chart of a binary search method for searching fortimes having optimal impedance values or changes.

FIG. 16 illustrates a method for optimizing an AA interval according toa maximum impedance change over the cardiac cycle.

FIG. 17 illustrates an alternative embodiment for optimizing an AAinterval indicated by a maximum impedance during the atrial cycle.

FIG. 18 is a flow chart illustrating an alternative method that may beused to optimize the AA interval according to a maximum impedance changeduring the atrial cycle.

FIG. 19 is a flow chart illustrating an embodiment implemented in anexternal programming device for providing impedance data to any of thepacing interval optimization methods described herein.

FIG. 20 is a flow chart illustrating an embodiment implemented in animplantable medical device for providing impedance data to the pacinginterval optimization methods described herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now to FIG. 1, there is shown a schematic representation of afour-chamber pacing system, illustrating four pacing leads providingbipolar electrodes positioned for pacing and sensing in each of therespective heart chambers, and also for impedance measurements. Pacinglead 38 is positioned conventionally such that its distal end is in theright ventricular apex position. It carries bipolar electrodes 38 a and38 b adapted for pacing and sensing; additionally, these electrodes canalso be used for impedance sensing as discussed below. Likewise, atriallead 36 is positioned so that its distal end is positioned within theright atrium, with bipolar electrodes 36 a, 36 b. Lead 34 is passedthrough the right atrium, so that its distal end is positioned in thecoronary sinus for pacing, sensing and impedance detection throughelectrodes 34 a, b, as shown. Likewise, lead 32 is positioned via thecoronary sinus a cardiac vein, e.g., the middle or great cardiac vein,so that distal electrodes 32 a and 32 b are positioned approximately asshown for pacing, sensing and impedance detection with respect to theleft ventricle. The pacing leads are connected to pacemaker 30 in aconventional manner.

It is to be understood that the impedance measurements include “raw”measurements and “processed” measurements. Processed measurementsinclude “average” measurements formed of the averages of more than onemeasurement, “filtered” measurements formed of filtered impedancemeasurements, “derivative” impedance measurements formed of the first orhigher order derivatives of impedance measurements, “selected” impedancemeasurements formed of the highest or lowest impedance measurements froma set of impedance measurements, and “inverted” impedance measurementsformed of inverted impedance measurements. The selected impedancemeasurements can be used to catch an impedance minimum or maximum from atime region including a small number, for example, 1 to 10, of impedancemeasurements. In embodiments having more than one pair of sensingelectrodes, two or more sensing electrode impedance measurements can beadded together to form an “augmented” impedance measurement. Similarly,one or more sensing electrode measurement can be subtracted from one ormore other sensing electrode measurement to form a “subtracted”impedance measurement. Both the augmented and subtracted impedancemeasurements can provide valuable information gathered from thesimilarities or differences encountered by the stimulating current'spath to the sensing electrodes. Unless noted otherwise, the impedancemeasurements used in all methods according to the present invention canbe any of the aforementioned raw and processed impedance measurementsand combinations thereof.

It also is to be understood that the system depicted here need not belimited to these lead positions, electrode sizes, and numbers ofelectrodes. Other embodiments of this system include multi-polarelectrodes (3 or more electrodes on a single lead), defibrillationcoils, and/or the pacemaker can. In some embodiments, the impedancemeasurement can be made between two or more stimulating electrodes andtwo or more sensing electrodes which are not necessarily exclusive ofeach other. Specifically, some of the stimulating electrodes may also besensing electrodes.

In some embodiments, the heart can be stimulated on one set ofelectrodes and recorded on two sets of electrodes. In one example, theheart is stimulated between the RV ring and the LV ring, and sensed by afirst electrode pair between the RV tip and the RA tip, and also sensedby a second electrode pair between the LV tip and the RA tip.

Referring now to FIGS. 2A and 2B, there is shown a simplified blockdiagram of a four channel pacemaker in accordance with this invention,having the capability of impedance detection to sense chamber filing,and valve movement of the left and right ventricles. It is to beunderstood that the impedance detection scheme may be used to detectmechanical events, such as ventricular wall contraction or ventricularfilling, in a known manner.

The system of FIG. 2A contains, in the pacemaker, a central processingblock 40, indicated as including timing circuitry and a microprocessor,for carrying out logical steps in analyzing received signals,determining when pace pulses should be initiated, etc., in a well knownfashion. Referring to the upper left-hand corner of the block diagram,there is shown signal amplifier circuitry 41, for receiving a signalfrom the right atrium. Electrode 36 a is illustrated as providing aninput, it being understood that the second input is received either frombipolar electrode 36 b, or via an indifferent electrode (the pacemakercan) in the event of unipolar sensing. Likewise, a pulse generator 42,acting under control of block 40, generates right atrial pace pulses fordelivery to electrode 36 a and either electrode 36 b or system ground.In a similar manner, right ventricular pace pulses are generated atoutput stage 43 and connected to electrode 38 a, and sensed rightventricular signals are inputted to sense circuitry 44, the output ofwhich is delivered to control block 40. Also illustrated is impedancedetector 45, which receives inputs from electrodes 36 a, 38 a, fordelivering information corresponding to ventricular volumes, whichtiming information is inputted into control block 40. Thus, the systemenables pacing and sensing in each chamber, as well as impedancedetection to provide an indication of degree of ventricular fillingduring diastole or emptying during systole.

Still referring to FIG. 2A, there are shown circuit components for theleft atrium and the left ventricle. Output generator stage 47, undercontrol of block 40, delivers left atrial pace pulses to stimulate theleft atrium through electrode 34 a and either electrode 34 b or systemground. Inputs from the left atrial lead are connected through inputcircuitry 46, the output of which is connected through to control block40. In a similar fashion, output stage 48, under control of block 40,provides left ventricular stimulus pace pulses which are deliveredacross electrode 32 a and either electrode 32 b or system ground; andleft ventricular signals are sensed from lead 32 and inputted to inputcircuit 49, which provides an output to block 40 indicative of leftventricular signals. Also, dual inputs from the left atrial electrode 34a and left ventricular electrode 32 a are inputted into left heartimpedance detector 50, which provides timing pulses to block 40indicative of ventricular volumes. With this arrangement, the pacemakerhas the basic timing and cardiac signal information required to programdelivery of pace pulses to respective heart chambers in accordance withthis invention. Block 40 contains current generators for use inimpedance detection; microprocessor or other logic and timing circuitry;and suitable memory for storing data and control routines.

Referring to FIG. 2B, there is shown a diagrammatic sketch of anarrangement for detecting left ventricular impedance change, which isprocessed in block 40 to obtain an indication of cardiac output. Asshown, a current source 52 provides a constant current source acrosselectrode 53 in the right atrium, which suitably can be electrode 36 a;and right ventricular electrode 54, which suitably can be electrode 38a. The current source can be pulsed, or it can be multiplexed in amanner as discussed below. Impedance sensors 57 and 58 provide signalsrepresentative of impedance changes therebetween, the impedance being afunction of blood volume, tissue between the electrodes, valveopen/closed states, and distance. The outputs from electrodes 57, 58 isconnected across impedance detector 56, which represents themicroprocessor and/or other processing circuitry in block 40 foranalyzing the impedance values and changes and making a determination ofcardiac output.

Referring now to FIG. 3, there is shown a block diagram of a pacemaker30 in accordance with a preferred embodiment of this invention, formultiplexing connections to electrodes so as to provide for pacing andsensing between any of the implanted lead electrodes, defibrillationcoils, or can, as well as for impedance determinations betweenrespective different lead electrodes. Reference is made to U.S. Pat. No.5,501,702, incorporated herein by reference, for a full discussion ofthis circuit, and in particular the multiplexing arrangement carried outby switch matrices 68, 70. The pacemaker 30 operates under control ofcircuitry 62, which may include a microprocessor or custom integratedcircuitry, as well as associated memory, in a manner well known in thepacemaker art. Circuitry 62 provides for processing of data, andgeneration of timing signals as required. Control circuitry 62 iscoupled to pace/sense circuitry 64, for processing of signals indicatingthe detection of electrical cardiac events, e.g., P-waves, R-waves, etc.sensed from conductors which connect electrically to electrodes 32 a-38b, as shown. The aforementioned leads are also coupled to a first switchmatrix 68 and a second switch matrix 70. Matrix 68 establishes aselectable interconnection between specific ones of the electrodes ofleads 32, 34, 36 and 38, and the current source 72, is controlled bycircuit 62. In a similar manner, switch matrix 70 establishes aselectable interconnection between lead conductors corresponding toselected electrodes, and impedance detection circuit 74, for the purposeof selecting impedance measurements.

With further reference to FIG. 3, current source 72 receives controlsignals on line 73 from circuitry 62, and is responsive thereto fordelivering constant current rheography pulses onto lead conductorsselected by switching matrix 68, which in turn is switched by signals onbus 83. Impedance detection circuit 74 is adapted to monitor the voltagebetween a selected pair of electrodes which pair is selectably coupledby operation of switch matrix 70, which in turn is switched by signalson bus 80. In this manner, circuit 74 determines the voltage, and hencethe impedance, existing between two selected electrodes. The output ofcircuitry 74 is connected through A/D converter 76 to control circuitry62, for processing of the impedance signals. The control of switchmatrix 68 through signals on bus 78, and the control of switch matrix 70through signals on bus 80, provides for multiplexing of differentimpedance signals.

It is to be understood that in the system arrangement of FIG. 3,pace/sense circuitry 64 may include separate stimulus pulse outputstages for each channel, i.e., each of the four-chambers, each of whichoutput stages is particularly adapted for generating signals of theprogrammed signal strength. Likewise, the sense circuitry of block 64may contain a separate sense amplifier and processor circuitry forsensed signals from each chamber, such that sensing of respective waveportions, such as the P-wave, R-wave, T-wave, etc. from the right heartand the left heart, can be optimized. The pulse generator circuits andsense circuits as used herein are well known in the pacemaker art. Inaddition, other functions may be carried out by the control circuitryincluding standard pacemaker functions such as compiling of diagnosticdata, mode switching, etc.

FIG. 4 illustrates an embodiment 300 for finding the time point ofminimum impedance between an A-event and V-event. The time of minimalimpedance can be used to set an optimal AV interval. Embodiment 300, andother AV and VV internal optimization methods disclosed in the presentinvention can be used in various settings, including a clinical settingwith breath hold, a clinical setting with respiration tracking andgating, a clinical setting with respiration filtering, and ambulatorysettings with breath hold, respiration tracking with gaiting, andrespiration filtering. These settings can be used as a precondition forobtaining the impedance measurements discussed with respect to method300, and, unless noted otherwise, other methods according to the presentinvention.

In Step 302, a long AV interval can be set. The long AV interval ispreferably an AV interval longer than physiologically appropriate forthe patient, for example two or three times longer. In a typicalpatient, the nominal AV interval may normally be about 100 milliseconds.One long AV interval can be about 300 or 200 milliseconds. In patientsnot being chronically paced, in a clinical setting, the implanted pacingdevice can be set to A-pace, then wait for the V sense. The long AVinterval allows the implanted pacing device an expanded period ofobservation.

In step 304, the atria can be sensed or paced. In step 306, the cardiacimpedance (Z) can be measured at multiple time points over the AVinterval until the V-pace or V sense events occur. Step 306 can measurethe impedance over numerous time points within the AV interval,searching for the time point having a minimum impedance. The minimumimpedance will correspond to the time of maximum expansion of theventricle, indicating the optimum time for contraction to occur. In somemethods, step 306 takes measurements at a large number of time pointsover a single AV interval. In other embodiments, step 306 takes a largenumber of impedance measurements over several successive cardiac cycleswith the same AV interval, to obtain an average impedance wave form overthe AV interval. In yet another embodiment, a small number of impedancemeasurements, as low as one, can be taken over successive cardiac cycleswith the same AV interval with the single or small number of impedancetime points being intelligently timed to effectively search for theimpedance minimum. The impedance minimum can be found by searching thewave form for a minimum, using methods well known to those skilled inthe art. In one method, a complete wave form is completed for the AVinterval, followed by searching the historical data for the minimumimpedance. A binary search can be performed on the wave form data, orthe slopes of wave form segments can be used to converge on theimpedance minimum.

In step 308, the optimal AV contraction time can be set equal to thetime point during the AV interval having the minimum impedance. In oneembodiment, the implanted pacing device can have the AV pacing intervalset equal to the time point having the minimal impedance, or the AVoptimal contraction time itself. In a preferred embodiment, in step 310,the cardiac electrical-mechanical delay between the pace and thecontraction is accounted for by offsetting the optimal contraction timewith a constant interval, allowing the pace event to lead the optimalcontraction time. In one embodiment, the offset is set to about 75milliseconds. In another embodiment, the offset is set to between about50 and 100 milliseconds. In still another embodiment, the offset is setto between about 25 and 200 milliseconds.

In some embodiments, the optimal AV interval thus obtained can be usedas a base interval to be further acted upon in demand pacing algorithms.In one method, method 300 is executed at substantially regularintervals, but not at every heartbeat. In one embodiment, method 300 isexecuted about every hour. In this embodiment, the long AV interval isset for one or a small number of heartbeats, followed by the cardiacimpedance measurements. In yet another embodiment, method 300 isexecuted when sleep is inferred from other indicators, for example,accelerometer readings and/or respiration readings.

The impedance measurement of embodiment 300 and the other methodsdiscussed in the present application, can be measured as a vector acrossthe best available leads present in the heart. In a bi-ventricularimplanted pacing device, the impedance can be measured between a rightventricular electrode and a left ventricular electrode disposed in acardiac vein. In one example, the impedance signal is stimulated betweenthe left ventricular ring and the right ventricular ring and detected bythe left ventricular tip and the right ventricular tip. The electrodepairs can be selected to maximize the impedance changes caused by theventricular contractions and expansions. In another embodiment, having aventricular lead, different electrodes disposed along the ventricularlead may be used to stimulate and sense the impedance vector.

FIG. 5A illustrates another embodiment 320A for optimizing the AVinterval. While method 300 attempted to maximize ventricular expansionas measured by the impedance minimum, method 320A attempts to maximizethe atrial contribution to ventricular filling as measured by the changein impedance between atrial activation and maximal ventricular volumebefore ventricular contraction. While method 300 could utilize aconstant AV interval during the search for minimum impedance, method320A actively varies the AV interval in the search for the optimal AVinterval.

In step 322, the AV interval can be initialized to an initial AVinterval value. In some embodiments, the AV interval is initialized toan initial AV interval believed to be optimal based on previousdeterminations.

In step 324, the atrium can be sensed or paced, then the ventriclepaced, using the current AV interval. In step 326A, the impedance can bemeasured at time points near A-event. In one method, the impedance ismeasured near the A-event, either shortly before or shortly after theA-event, preferably shortly after the A-event. The impedance can bemeasured again near the V-pace event, either shortly before, during, orafter the V-pace. The impedance measurement taken near the V-pace shouldcorrespond to the maximum expansion and minimum impedance. The impedancewill normally drop from the A-event to the V-pace.

In some embodiments, step 326A measures the impedance over N beats,where N can be one or greater. The impedance data thus obtained can beaveraged to obtain an average impedance minimum and maximum for the sameAV interval. In another method, taking impedance measurements for thesame AV interval over N beats, the delta Z itself can be averaged overseveral beats having the same AV interval.

In step 328A, the delta Z, the difference between the maximum impedanceand the minimum impedance measured, can be determined. In decision step330, the determination can be made whether the AV interval causing themaximum delta Z has been found, and the search completed. As will bediscussed further, different algorithms can be used to determine whetherthe searching for the optimal delta Z by varying the AV interval hasbeen completed or requires further iteration. In step 330, if themaximum delta Z has not yet been found, then step 334 can be executed tosearch further for the maximum delta Z by changing the AV interval. Thesearch algorithms used will be discussed below. In step 334, the AVinterval can be changed to intelligently bracket the maximum delta Z andsearch for the maximum delta Z. The search and the changing of the AVinterval can be based upon the recent history of previous valuesobtained for various AV intervals. If the maximum delta Z has not beenfound, after changing the AV interval at 334, step 324 can be executedusing the new AV interval.

The above discussed steps can be repeated until step 330 determines thatthe maximum delta Z has been found, or the algorithm times out. When themaximum delta Z has been found at 330, step 332 can be executed to setthe paced AV interval to the AV interval corresponding to the maximumdelta Z. As previously discussed, the impedance measured in step 326A ispreferably measured using a sub-threshold pulse, rather than a pacingpulse. In an alternate embodiment, the pacing pulse is used to measureat least one of the impedance values near the minimum and/or maximum.

FIG. 5B illustrates another embodiment 320B for optimizing the AVinterval. While method 320A attempted to maximize the impedance drop,from A-event to V-pace, method 320B attempts to maximize the increase inimpedance from a minimum, usually near V-pace, to a maximum, locatedbetween the V-pace and the next A-event. Identically numbered steps inmethod 320B and 320A, have already been discussed with respect to method320A in FIG. 5A, and will be repeatedly discussed.

In step 326B, the impedance can be measured at time points from nearV-pace until near A-event, in order to catch the peak or maximumimpedance located between the two events. In one method, the impedanceis measured near the V-pace, either shortly before, during, or shortlyafter the V-pace, until either the maximum impedance is detected oruntil the A-event is detected, with the maximum impedance having beencaptured.

In some embodiments, step 326B measures the impedance over N beats,where N can be one or greater. The impedance data thus obtained can beaveraged to obtain an average impedance minimum and maximum for the sameAV interval. In another method, taking impedance measurements for thesame AV interval over N beats, the delta Z itself can be averaged overseveral beats having the same AV interval.

In step 328B, the delta Z, the difference between the maximum impedanceand the minimum impedance measured, can be determined. As previouslydiscussed, in some methods, the impedance near V-pace is used in placeof a minimum measured impedance, as the impedance near V-pace istypically very low.

FIG. 6 includes a flow chart for embodiment 340, which varies the VVinterval to find the maximum impedance. The maximum impedancecorresponds to the maximum ventricular contraction and minimumventricular volume. Method 340 optimizes the VV interval indicating theamount of time by which the right ventricle leads or lags the leftventricle. The VV interval may also be viewed as having a separateatrium to right ventricle delay and a separate atrium to left ventricledelay. The VV interval may also be referred to as the inter-ventricletime difference.

In step 341, the VV interval can be initialized in some methods to 0. Instep 342, the AV interval can be initialized and maintained at aconstant, preferably, optimal AV interval. In some methods, the optimalAV interval as determined by methods such as method 300, 320A, or 320Bcan be used to set the optimal AV interval.

In step 344, the atrium A-event occurrence can be paced or sensed, thenthe first ventricle paced, then the second ventricle paced, using the AVinterval from step 342 and the VV interval. Whether the right ventricleis the first ventricle or the left ventricle is the first ventriclepaced depends upon whether the right ventricle leads or lags the leftventricle, respectively. In a preferred embodiment, the AV intervalrefers to the time delay between the RA-event and the LV-pace. In otherembodiments, the AV interval refers to the time delay between theRA-event and the first V-pace or to the time delay between the RA-eventand the second V-pace, while in still other embodiments, the AV intervalrefers to the time delay between the RA-event and the average betweenthe two V-paces.

In step 346, the impedance can be measured at multiple times. In onemethod, the impedance is measured at one or more times shortly after aV-pace and at one or more times either shortly before, during, orshortly after the next A-pace event, in order to catch the cardiac cyclemaximum impedance, as previously described. As previously discussed,while the impedance can be measured using pacing signals, separate, subthreshold signals are used in a preferred embodiment. In anotherembodiment of the invention, the impedance is measured at multiple timesafter a V-pace until the next A-event to determine the maximumimpedance. The impedance at or near a V-pace can be used in place of theminimum impedance, as previously discussed, in some methods. Measuringstep 346 can be repeated for the same VV interval for a number ofconsecutive beats in order to obtain an average for the maximumimpedance value found. An averaged waveform, averaged over severalcardiac cycles, can also be used to determine the maximum impedance.

In step 348, the maximum impedance found for the VV interval can bedetermined. As previously discussed, the maximum impedance correspondsto the state of maximum ventricular contraction, indicating theventricles have emptied. The maximum impedance found in step 348 is themaximum impedance found for the current VV interval.

In decision step 350, a determination is made as to whether the VVinterval causing the maximum impedance has been found for the allowablerange of VV intervals. The algorithms and search methods, which can beused in combination with method 340, are discussed in more detail below.If step 350 determines that the VV interval having the maximum impedancehas not been found, then step 354 can be executed to further search forthe maximum impedance by changing the VV interval. Step 354 can changethe VV interval, preferably using the recent history of impedances foundfor other VV intervals. Step 354 can intelligently search for theoptimal VV interval by bracketing the maximum impedance based on therecent history of impedance values found. Using the new VV intervalfound in step 354, step 342 can be executed.

When decision step 350 determines that the VV interval having themaximum impedance has been found, then step 352 can be executed to setthe pacing VV interval to the VV interval corresponding to the maximumimpedance found. In some methods, after step 352, AV intervaloptimization methods such as method 300 or 320 can be executed tore-optimize the AV interval using the W interval recently optimized. TheAV interval may thus be optimized while maintaining a time differencebetween the V-pace for the right ventricle and the V-pace for the leftventricle.

In FIG. 7, method 360 is used to optimize the VV interval. As usedherein, the VV interval refers to the delay between the pacing of theright ventricle and the left ventricle. The VV interval may also bereferred to as the inter-ventricle time difference or timing difference.The VV interval may thus be positive or negative, depending on whetherthe right ventricle leads or lags the left ventricle. As previouslydiscussed, method 360 may be executed in the various clinical andambulatory settings having various preconditions, which will bediscussed later.

In step 361, the VV interval can be initialized to a time, which is 0 insome methods. In step 362, the AV interval can be set to a constant,preferably an optimal AV interval as determined by methods such asmethod 300 of FIG. 4, method 320A of FIG. 5A or method 320B of FIG. 5B.

In step 364, the atrium can be sensed or paced, followed by the firstventricle being paced, followed by the second ventricle being paced.Step 364 can thus use the AV interval of step 362 and an initial VVinterval. In some methods, the VV interval is initially set to zero. Insome methods, the AV interval as used in method 360 refers to the timingbetween the A-event and the first ventricle V-pace, while in othermethods the AV interval refers to the timing between the A-event and thesecond V-pace, while in still other methods, the AV interval refers tothe time delay between the A-event and the average time of theventricular paces. Depending on the VV interval, either the right or theleft ventricle may be the first or second ventricle, respectively. Aspreviously mentioned, the VV interval can be a positive or a negativenumber in some implementations of the method.

In step 366, the impedance can be measured at multiple times. In onemethod, the impedance is measured at one or more times shortly after aV-pace and at one or more times either shortly before, during, orshortly after the next A-event, in order to catch the cardiac cyclemaximum impedance, as previously described. As previously discussed,while the impedance can be measured using pacing signals, separate, subthreshold signals are used in a preferred embodiment. In anotherembodiment of the invention, the impedance is measured at multiple timesafter a V-pace until the next A-event to determine the maximumimpedance. The impedance at or near V-pace can be used in place of theminimum impedance, as previously discussed, in some methods. Measuringstep 366 can be repeated for the same VV interval for a number ofconsecutive beats in order to obtain an average for the maximumimpedance value found. An averaged waveform, averaged over severalcardiac cycles, can also be used to determine the maximum impedance.

In step 368, the change in impedance for this VV, delta Z, can bedetermined by taking the difference between the maximum impedance andthe minimum impedance. In step 370, the determination can be made as towhether the maximum change in impedance over a range of VV intervals hasbeen found, and the search complete. The exact nature of the manypossible algorithms used to make this determination are discussed below.If the VV causing the maximum delta Z has not been found, then thesearch can be continued by changing the VV interval, and proceeding tostep 362. The VV interval is preferably changed based on the recenthistory of impedances obtained for other VV intervals. This process cancontinue until decision step 370 makes the determination that themaximum delta Z has been found, or the algorithm times out. When themaximum delta Z has been found, step 372 can be executed. In step 372,the VV interval can be set to the VV interval corresponding to themaximum delta Z. In some embodiments, the AV interval can bere-optimized using methods such as method 300 or 320, previouslydiscussed.

The impedance signal used to measure the change in degree of contractionand expansion of the heart is typically a composite signal. Thecomposite signal has a low frequency, large amplitude impedance changecontribution from the breathing of the patient. The impedancemeasurement is greatly affected by the distance between the measuringelectrodes. The distance between the measuring electrodes is greatlyaffected by the breathing. The breathing contribution has a nominallysinusoidal wave form having a period of between about 5 and 10 breathsper minute. In contrast, the cardiac contribution to the impedancechange has a smaller amplitude and a nominal period of about 60 beatsper minute. The smaller amplitude, higher frequency cardiac impedancewave form is thus superimposed on the larger amplitude, slower frequencybreathing impedance wave form. The contribution of breathing can becompensated for using varying methods.

FIG. 8 illustrates an embodiment 400 for providing impedance data, tothe interval optimization methods previously discussed. Method 400 isone example of a method for providing impedance data, which ispreferably used in a clinical setting. In step 402, method 400 waits fora start signal. The patient is preferably supine, not moving, and has aregular breathing pattern. A treating physician can wait for the patientto be appropriately disposed then send a start signal from a programmingunit, through a telemetry link, to the implanted pacing device. In step402, the pacing device receives the start signal from the programmer,and proceeds to step 404.

In step 404, the implanted pacing device can automatically adjust pacingparameters as needed to carry out the interval optimization methodspreviously discussed to measure the impedance changes over one or moreheartbeats. In the example illustrated, the impedance is measured over asingle beat. With the impedance measured over one beat, decision step406 is executed, checking for the existence of a stop condition. If thestop condition is not found, step 404 can be executed, to gather datafrom another heartbeat or beats. In a preferred method, the start signalis not sent until the patient is both supine, not moving, and further,has temporarily held their breath. In one example method, the treatingphysician instructs the patient to hold their breath, and uponobservation of the breath holding, sends the start signal. In someembodiments, the stop condition at step 406 consists simply of a timeror heartbeat counter, which gathers data over a certain time interval ofheartbeats or number of heartbeats. In another embodiment, a largedegree of patient movement as determined by an accelerometer and/or alarge change in impedance indicating breathing may be used to initiatethe stop condition at step 406. After one or more beats has beenmeasured for impedance at step 404, and the data gathering stopped, step408 can be executed. In step 408, the measured impedance can be providedto one of the AV or VV optimization methods previously described.

FIG. 9 illustrates another embodiment 420 for providing impedance datato the optimization methods previously discussed. Method 420 is similarto method 400 previously discussed, but waits for a detected breath holdas an integral part of the algorithm rather than depending upon thephysician to observe the breathing cessation. In step 422, the methodwaits for the start signal, for example, from a programmer unitcommunicating to the implanted device via a telemetry link.

In step 424, the logic waits for a breath hold. Breath holding may bedetected by any of a number of methods. In one method, the impedancedata is tracked and filtered to detect the long period impedance changesof large amplitude, indicative of breathing. In another method, animpedance measurement to detect breathing is used that is different fromthe impedance measurement used to optimize the AV and VV intervals. Inone example, a transthoracic impedance between the implanted pacingdevice housing and a cardiac lead are used to detect breathing. In stillanother embodiment, an accelerometer, for example, based either in thehousing or on a lead, is used to detect breathing.

When the breath hold is detected in step 424, step 426 can be used tomeasure the impedance changes, as the impedance changes due to thepumping of the heart are more easily measured without the largerbreathing contribution. In decision step 428, if breathing is stillceased, and no stop condition is detected as decision step 430,impedance can be measured at step 426 for another beat or another timeperiod. As previously discussed, a stop condition such as at step 430can be the detection of bodily movement as detected through anaccelerometer, the expiration of a timeout period, the successfulsampling of a maximum number of beats, or an abnormally high change inimpedance. Step 426 can thus be executed for a number of beats. When therequired number of beats has been measured for impedance and/orbreathing has resumed, the measured impedance can be fed to one or moreof the optimization methods previously discussed. The logic inembodiment 420 may be executed several times in succession, feeding newimpedance data to one of the AV or VV optimization algorithms previouslydiscussed. Specifically, the breathing contribution to impedance iscompensated for by a temporary holding of breath, providing a constantcontribution to impedance by the breath hold.

FIG. 10 illustrates yet another embodiment 440 for providing impedancedata to the AV and VV interval optimization methods previouslydiscussed. In step 442, the composite impedance wave form is measured,preferably over several breathing cycles. The composite impedance thushas the higher frequency cardiac impedance change wave form superimposedon the lower frequency, larger amplitude breathing impedance change waveform.

In step 444, the breathing contribution to the composite impedance waveform can be obtained by filtering or smoothing the composite wave formto obtain the breathing impedance wave form alone. Other suitablemethods, well known to those in the signal processing arts, can be usedto separate the breathing impedance wave form from the cardiac impedancewave form.

In step 446, the breathing contribution can be removed from thecomposite wave form to obtain the cardiac impedance wave formcontribution. Other methods well known to those in the signal processingarts can be used to obtain the higher frequency cardiac impedance waveform from the composite wave form. In step 448, the cardiac impedancecontribution can be provided to one or more of the interval optimizationmethods previously discussed.

FIG. 11 illustrates a flow chart of embodiment 460 which can be used toselect periods of breath holding in order to obtain cardiac impedancechange data that is less effected by breathing. In step 462, thebreathing can be tracked over several breathing cycles. This trackingcan be done using various devices and methods, not necessarily using thesame methods and/or sensors used to measure the cardiac impedance. Insome examples, implanted cardiac device housing based accelerometers orlead based accelerometers can be used to track breathing apart from theimpedance measurement. In a clinical setting, a belt disposed about thepatient's chest can be used to sense breathing as can a pressure or heatsensitive device disposed near the mouth and/or nose. Other devices fortracking breathing, commonly used in demand or physiologically basedpacing, can be used to track breathing as well.

In step 464, a breath hold can be awaited. When a breath hold has beendetected at step 464, the impedance can be measured for a number ofbeats or a number of time intervals while there is still no breathingdetected, at step 466. After the required number of beats or timeintervals has elapsed and/or breathing has been detected, the cardiacimpedance change data can be collected at step 468 and used in one ofthe AV or VV interval optimization methods previously discussed. Method460 thus illustrates a method, which can be used to optimize AV or VVintervals by the patient holding their breath for a required period toinitiate the optimization procedure.

FIG. 12 illustrates another embodiment 480 which can be used to provideimpedance data to the interval optimization methods previouslydiscussed. Method 480 illustrates a method using selection or “gating”during appropriate parts of the breathing cycle to obtain good impedancedata. In method 480, impedance data are obtained near the peak of theinspiration and/or nadir of the expiration phase regions, which are lesseffected by respiratory changes to the impedance signal. In step 482,breathing can be tracked over several breathing cycles, using devicesand methods previously discussed, including accelerometers andtransthoracic impedance measurements. In some methods, a monitoringrange or window is used. This range is defined as a time window aroundthe peak or nadir or other time point on the respiration cycle in whichthe respiration changes are small. One method uses the observation thatthe first derivative of the respiration signal can be taken to see whenrespiration changes are at a minimum. In step 484, the method waits forbreathing expiration. In some methods, breathing inspiration can also beused. As the monitoring range is detected, step 486 can be executed tomeasure the impedance changes for N beats or N time periods while stillin the monitoring range. Numerous submethods can be used to detect thenadir of the respiration cycle. The impedance measurement can be takenfrom a monitoring window or range in which the respiration component isrelatively small.

FIG. 13 illustrates an embodiment 500 for optimizing heart pumpingoperations generally. In step 502, the AV interval is selected tooptimize heart pumping action. After initially optimizing the AVinterval, step 504 is executed to optimize the VV interval. With the VVinterval selected to optimize cardiac output, step 506 is executed toonce again optimize the AV interval while using the VV interval providedby step 504. In one example, methods such as method 300, 320A, or 320Bare used to optimize the AV interval using a VV interval of zero in step502. In step 504, methods such as method 340 or 360 are used to select aVV interval for optimal cardiac output. With the VV interval selected,the right ventricle will either lead or lag the left ventricle, for anon-zero VV interval.

In step 506, embodiments such as embodiment 300, 320A or 320B can beonce again executed, this time incorporating an optimal VV interval.Thus, the AV interval utilized in method 300 or 320 will include theright ventricle and the left ventricle being paced at different times.In one example, the AV interval thus optimized will refer to the A tofirst interval delay while in other methods, the AV interval will referto the atrial to second interval delay, while in still otherembodiments, the atrial to ventricle period will refer to the atrial toaverage ventricular pace time. In this way, using method 500, the AVsynchrony can be still further optimized.

FIG. 14 illustrates a search embodiment 480 which can be used in variousembodiments of the present invention. In particular, method 480 can beused in steps such as step 330 and 334 of method 320A and 320B, steps350 and 354 of method 340, and steps 370 and 374 of method 360.

In one embodiment, method 480 operates as a “binary search.” In methodssuch as method 300, a wide variety of search algorithms can be used as anumber of impedance values may be provided over the cardiac cycle. Inmethods 320A, 320B, 340 and 360, however, the ventricle or ventriclescan be paced only once per cardiac cycle, thus benefiting from a moreintelligent search.

In step 482, a search interval can be initialized to an initial searchinterval. The search interval may be viewed as the interval between thetime points which will be spaced within the longer time window of allthe maximal possible AV or W interval. In one example, the initialsearch interval may be about 40 or 20 milliseconds. In step 483, thecenter point is set as bisecting the search interval. In step 484, thesearch interval minimum can be set to indicate the required lower limiton the search interval in order to satisfy the search completionrequirement. In other words, when the search has found a minimum ormaximum, and the search interval is sufficiently small, then the searchwill be considered complete, and the overall minimum or maximum will beconsidered as found. In contrast, if a minimum or maximum has been foundbut the search interval is large, for example, 50 milliseconds, thesearch will likely continue in many embodiments to find a more accuraterepresentation of the timing leading to the minimum or maximum. In oneembodiment, the search interval minimum is set to about 5 milliseconds.

In step 486, impedance is measured and/or pacing is performed at endpoints separated by the search interval centered about a center point.In the example of a binary search, pacing may occur at three differenttime points separated by the search interval and separated about thecenter time point. In the example of a binary search having a centertime point of 100 milliseconds and a search interval of 40 milliseconds,the three time points will be 60 milliseconds, 100 milliseconds, and 140milliseconds. The allowable range of time points may of course beclamped at safety limits at either end. In the case of a binary search,having three time points, there will be formed two segments, one eachextending from an end point toward the center point. In the operation ofthe algorithm, it is not known a priori where the maximum or minimumwill be. Where the step 486 is pacing at end points, step 486 will beexecuted over several heartbeats. In embodiments where averaging isused, even more heartbeats will be used as the same pacing time pointwill be executed for multiple heartbeats.

In step 488, the time point having the minimum or maximum, depending onthe embodiment, will be noted. The time point is thus the minimum ormaximum of the end points measured and/or paced in step 486.

In decision step 490, it is determined whether the time point of minimumor maximum impedance is an end time point. If the minimum or maximumoccurs at an end point, the true minimum or maximum may lay beyond theend point, and further searching is required. In this case, executionproceeds to step 496, where the center point of the next search iscentered at or toward the time point of minimum or maximum found in step488. In some methods, the new center is slewed toward the time point ofminimum or maximum impedance, while in other embodiments, the centerpoint is set exactly at the time point of minimum or maximum impedance.

With the next search properly centered, the search interval can bedecreased or left the same. In one embodiment, the search interval isunchanged when the search window is effectively moving sideways, ratherthan converging on the minimum or maximum. In the binary search example,having a search centered at 100 and sampling or pacing at 140 and 60milliseconds, if the minimum or maximum was located at 140, the nextsearch could be centered about 140 and extending up to 180 and down to100. In a preferred embodiment, time points representing previouslyvisited points are recalled from memory rather than being resampled orrepaced. In another method, the end points of step 486 are resampledand/or repaced at each execution of step 486.

Embodiment 480 thus executes from step 490 through 496 until a minimumor maximum is found that is not an end point. When a minimum or maximumis found that is not an end point, then decision step 492 can beexecuted. In some embodiments, a specific degree of centrality isrequired to execute 492. For example, in some embodiments, the locatedmaximum or minimum time must be the absolute center of the searchinterval or at least be the central point.

In decision step 492, a determination is made where the search intervalis sufficiently small to end the search. In particular, it can bechecked whether the search interval is less than or equal to the minimumsearch interval. In one example, in order to successfully complete thesearch, the search interval must be 5 milliseconds or less. If thesearch interval is not sufficiently small, execution can proceed to step494 where the search interval is decreased. In one example, the searchinterval is halved in step 494. Proceeding to step 496, the center pointcan be set to the, or toward the, time point corresponding to theminimum or maximum impedance found in step 488. In some embodiments,step 496 thus centers the search for the same number of points and thesame center search point as the previous execution of step 486, but witha small search interval. As previously discussed, in some embodiments,the measurement and/or pacing at a time point is not revisited if thetime point has been measured and/or paced recently. In theseembodiments, the impedance or impedance change value can be retrievedfrom recent memory. In other embodiments, all end points are revisitedin step 486.

When the search interval lower limit has been satisfied in step 492,step 498 can be executed. The desired minimum or maximum impedance orimpedance change can be provided in step 498 and utilized by the methodsto optimize the AV or VV intervals previously discussed.

Embodiment 480 is a general algorithm which can be used to rapidlybracket or converge on the minimum impedance, maximum impedance, ormaximum impedance change. A variation on method 480 may be brieflydescribed. In step 496, the center point for the next search may also beestablished by interpolating between the best impedance value found andthe next best impedance value found. In one example, searching for theimpedance maximum, the time point of the maximum impedance and the timepoint of the next highest impedance may be interpolated between toobtain the new center point for the search. Similarly, in a search foran impedance change maximum, the pace time having the maximum impedancechange and the pace time having the second maximum impedance change maybe used and the new center point for the next V-pace may be interpolatedbetween the two points.

In another embodiment of the invention, a binary search embodiment, theinitial interval is divided by one point into two search segments. Thebest point is noted, as is the next best point. If the best point is anend point, the search is shifted over, making the previous end point thecenter point, and the search evaluated again. If the best point is acenter point, but the search interval lower limit is not satisfied, thenthe next search subdivides the segment between the best point and thenext best point and evaluates the impedance there. The search intervalis thus half the search interval as the previous search interval. If thepoint evaluated midway between the previous best point and next bestpoint is again the local maximum, and the search interval issufficiently small, then the search is complete, and the optimalinterval has been found. If the most recently evaluated point is not thebest point, then the segment between the best point and the worst pointis subdivided and the best point again search for among the points.

The present invention can use a binary search algorithm to find theminimum impedance, the maximum impedance, or the maximum impedancechange over a window of time values, from low to high. As the method canbe used with goal of finding the time point having the best impedancevalues generally, whether minimum, maximum, or maximum change, themethod may be explained generally in terms of finding the bestimpedance. Several binary search variations can be used. In general, thebinary search starts with a set of three time points, low, middle, andhigh, having low, middle, and high time values, respectively, separatedby a search time interval. The three time points divide the time rangeinto two subintervals, from low time to middle time, and from middletime to high time. The binary search, explained generally, starts withinitial high and low time points, and a lower limit search interval timeor goal.

One embodiment evaluates impedance at the three time points, low,middle, and high, separated by the time search interval. If the “best”impedance is found at the middle point and the search interval is lessthan or equal to the lower limit search interval goal, then the middletime point can be returned as the time point having the best impedance.If the best impedance is found at the middle point and the searchinterval is greater than the lower limit search interval, then thesearch interval can be halved, and the search repeated using as the newmiddle point the point midway between the old middle point and thesecond best time point.

In the case where the best impedance is found at one of the end points,then the search interval is unchanged, and the search is repeatedcentered on the new end point, effectively sliding the search windowover in time. In this way, the method can use the optimal time pointsfrom previous optimizations as the initial first estimate at the besttime point for a later optimization, yet remain sufficiently robust toslide the search window over when the current optimal time is locatedoutside of the initial search window.

FIG. 15 illustrates a binary search embodiment 550, starting at aninitialization step 552, initializing two time points T1 and T2, whichcan the low and high time points of the search window, in any order. Theimpedance (Z) can be evaluated for both T1 and T2. In one embodiment,the impedance for a time point is referenced by a function or array,where the actual sensor value is retrieved only if there is no recentsensor value for that time point.

In step 554, a middle time point, MID is set to bisect T1 and T2, beingset equal to (T1+T2)/2. The current search interval, INTER, is set equalto half the distance between T1 and T2, and is the length of each of thetwo segments created by MID to T1 and MID to T2. The impedance can beevaluated at MID.

In decision step 556, if the search interval INTER is sufficiently low,then the search goal is met, the search is done, and step 558 isexecuted. In step 558, the best impedance value can be returned. In somemethods, the middle time point MID is returned as having the time ofbest impedance. In other methods, the best of the time points T1, MID,and T2 is determined, with the best of the three returned as the timepoint of best impedance.

If the search is not complete, then step 560 is executed, to determineif the middle time point MID had the best impedance. If the bestimpedance was at MID, then step 564 is executed, to determine which ofT1 and T2 was second best. If T1 was second best, then T2 is set to T1,and T1 is set to MID. If T2 is second best, then T1 is set to MID, andT2 remains unchanged. Step 554 can be executed once more, now using asearch interval half the size, and bisecting the segment between MID andthe second best point.

If decision step 560 determines that MID is not the best, then the bestimpedance is at an end point, and decision step 570 executes todetermine if T1 is best. If T1 has the best impedance, then at step 578,T2 is set to T1 minus the current search interval INTER, and T1 is setto T1 plus the current search interval INTER. If T2 is best, then atstep 572, T1 is set to T2 plus the search interval and T2 is set equalto T2 less the search interval. The new time points are set to bracketthe end point that was the best point, with the search intervalunchanged, and the search window slid over, to search again. It shouldbe noted that in some binary search methods, execution does not branchon whether the best point is an end point, rather than the middle, withone of the segments being bisected regardless and the search continued.In this method, execution path 564 may be viewed as always being taken,and path 562 is effectively never taken.

FIG. 16 illustrates an embodiment 600 for optimizing an AA interval. TheAA interval refers to the interval between a right atrial event and aleft atrial event during bi-atrial pacing. The AA interval may also bereferred to as the inter-atrial time difference. Bi-atrial pacing can bebeneficial in patients having inter-atrial block and in three orfour-chamber cardiac resynchronization pacing. The AA interval may bedefined relative to either the right or left atrium and will determinewhether the right atrium leads or lags the left atrium. Method 600 canbe executed in various clinical and ambulatory settings under variouspreconditions. Method 600 varies the AA interval to determine the AAinterval that results in maximum change in heart volume as measured by amaximum impedance change over the cardiac cycle. The AA intervalproducing maximum ventricular filling and thereby resulting in maximumventricular ejection is desired.

In step 602, the AA interval is initialized to an initial AA intervalvalue, which may be equal to zero. In some embodiments, the AA intervalis initialized to an initial AA interval believed to be optimal based onprevious determinations. In the presence of three or four chamberpacing, the AV and VV intervals are set at step 604 to constant valueswhich may be nominal values, values based on previous optimizationmethod results, or correspond to the current AV and VV intervalssettings. In some methods, the AV interval as used in method 600 refersto the timing between the first A-event and the first ventricle V-pace,while in other methods the AV interval refers to the timing between thefirst A-event and the second V-pace, while in still other methods, theAV interval refers to the time delay between the average time of atrialevents and the average time of the ventricular paces.

In step 606, the first atrial chamber is sensed or paced, then thesecond atrial chamber is paced using the current AA interval. Typically,the right atrial chamber will be paced or sensed first followed by apacing pulse delivered in the left atrium at the chosen AA interval.These atrial events are followed by a ventricular event in eachventricle, which may be paced or sensed events. A ventricular pace maybe delivered in the first ventricle using the current AV interval. Asensed or paced event in the first ventricle may be followed by aventricular pace in the second ventricle using the current VV intervalif bi-ventricular pacing is enabled.

In step 608, the cardiac impedance is measured at time points near thelast V-event, either shortly before, during, or shortly after theV-event. The impedance is measured again near the first A-event, eithershortly before, during, or after the A-event. The impedance measurementtaken near the V-event should correspond to the maximum expansion of theventricles and minimum impedance. The impedance measurement taken nearthe A-event should correspond to maximum contraction of the ventriclesand a maximum impedance. As previously discussed, the impedance measuredin step 608 is preferably measured using a sub-threshold pulse, ratherthan a pacing pulse. In an alternate embodiment, the pacing pulse isused to measure at least one of the impedance values near the minimumand/or maximum.

In some embodiments, step 608 measures the impedance over N beats, whereN can be one or greater. The impedance data thus obtained can beaveraged to obtain an average impedance minimum and maximum for the sameAA interval. In another method, taking impedance measurements for thesame AA interval over N beats, the delta Z itself can be averaged overseveral beats having the same AV interval.

In step 610, the delta Z, the difference between the maximum impedanceand the minimum impedance measured for an AA interval, is determined. Indecision step 612, the determination is made whether the AA intervalcausing the maximum delta Z has been found, and the search completed. Asdescribed previously, different algorithms can be used to determinewhether the searching for the optimal delta Z has been completed orrequires further iteration by varying the AA interval. In step 612, ifthe maximum delta Z has not yet been found, then step 614 can beexecuted to search further for the maximum delta Z by changing the AAinterval. The search algorithms described previously may be utilized. Instep 614, the AA interval can be changed to intelligently bracket themaximum delta Z and search for the maximum delta Z. The search and thechanging of the M interval can be based upon the recent history ofprevious values obtained for various AA intervals. If the maximum deltaZ has not been found, the AA interval is changed to a new AA interval atstep 614, and step 606 can be executed using the new AA interval.

The above discussed steps can be repeated until step 612 determines thatthe maximum delta Z has been found, or the algorithm times out. When themaximum delta Z has been found at 610, step 616 can be executed to setthe paced AA interval to the AA interval corresponding to the maximumdelta Z. It is expected that the AA interval associated with a maximumdelta Z measured over the cardiac cycle corresponds to the AA intervalproducing the greatest atrial contribution to ventricular filling(maximal expansion and minimum impedance) which in turn results in thegreatest ventricular ejection (maximal contraction and maximumimpedance).

FIG. 17 illustrates an alternative embodiment 620 for optimizing an AAinterval indicated by a maximum impedance. In this embodiment, theimpedance signal measured is sensitive to changes in atrial volume.Impedance measuring electrodes are selected such that atrial volumechanges can be assessed by the impedance signal. Determination of an AAinterval corresponding with a maximum impedance measurement obtainedduring the atrial cycle will correspond to a maximum atrial contraction(minimum atrial volume), and therefore correspond to the maximum atrialcontribution to ventricular filling.

In step 622, the AA interval is initialized, in some methods to 0. Instep 624, the AV and VV interval are initialized and maintained at aconstant, value, which may be previously determined optimal AV and VVintervals. In some methods, the optimal AV interval as determined bymethods such as method 300, 320A, or 320B (FIG. 4, 5A and 5B,respectively) can be used to set the optimal AV interval. The optimal VVinterval as determined by methods such as method 340 or 360 (FIGS. 6 and7, respectively) can be used to set the optimal VV interval.

In step 626, the first atrial chamber is sensed or paced, and then thesecond atrial chamber is paced using the current AA interval. Typically,the right atrial chamber will be paced or sensed first followed by apacing pulse delivered in the left atrium at the chosen AA interval.These atrial events are followed by a ventricular event in eachventricle, which may be paced or sensed events. A ventricular pace maybe delivered in the first ventricle using the current AV interval. Asensed or paced event in the first ventricle may be followed by aventricular pace in the second ventricle using the current VV intervalif bi-ventricular pacing is enabled.

In step 628, the impedance is measured after the A-pace event in thesecond atrial chamber at one or more time points occurring prior to thefirst V-event. In one method, the impedance is measured at one or moretimes after the A-pace delivered in the second atrial chamber and at oneor more times either shortly before, during, or shortly after the nextV-pace event, in order to catch the atrial cycle maximum impedance. Inanother embodiment of the invention, the impedance is measured atmultiple times after the A-pace in the second atrial chamber until thenext V-event to determine the maximum impedance during the atrial cycle.Measuring step 628 can be repeated for the same AA interval for a numberof consecutive beats in order to obtain an average for the maximumimpedance value found. An averaged waveform, averaged over severalcardiac cycles, can also be used to determine the maximum impedance. Aspreviously discussed, while the impedance can be measured using pacingsignals, separate, sub-threshold signals are used in an exemplaryembodiment.

In step 630, the maximum impedance found for the current AA interval isdetermined. As previously noted, the maximum impedance measured duringthe atrial cycle corresponds to the state of maximum atrial contraction,indicating the maximum atrial contribution to ventricular filling.

In decision step 632, a determination is made as to whether the AAinterval causing the maximum impedance has been found for the allowablerange of AA intervals. The algorithms and search methods which can beused in combination with method 620 have been described previously. Forexample search method 480 or method 550 (FIGS. 14 and 15, respectively)may be used to determine if the AA interval causing the maximumimpedance during the atrial cycle has been found. If step 632 determinesthat the AA interval having the maximum impedance has not been found,then step 634 can be executed to further search for the maximumimpedance by changing the AA interval. Step 634 can change the AAinterval using the recent history of impedances found for other AAintervals. Step 634 can intelligently search for the optimal AA intervalby bracketing the maximum impedance based on the recent history ofimpedance values found. Using the new AA interval found in step 634,step 626 can be executed.

When decision step 632 determines that the AA interval having themaximum impedance has been found, then step 636 can be executed to setthe pacing AA interval to the AA interval corresponding to the maximumimpedance found. In some methods, after step 636, AV and/or VV intervaloptimization methods can be executed to re-optimize the AV or VVinterval using the AA interval recently optimized. The AV or VVintervals may thus be optimized while maintaining an optimized timedifference between the A-pace for the right atrium and the A-pace forthe left atrium.

FIG. 18 is a flow chart illustrating an alternative method 640 that maybe used to optimize the AA interval according to maximum atrial ejectionmeasured by a maximum impedance change during the atrial cycle. In step642, the AA interval can is set to an initial value, which is zero insome methods. In step 644, the AV and VV intervals can be set to aconstant, which may be a previously determined optimal interval. The AVinterval may be set according to the result determined by optimizationmethods such as method 300 of FIG. 4, method 320A of FIG. 5A or method320B of FIG. 5B. The optimal VV interval as determined by methods suchas method 340 or 360 shown in FIGS. 6 and 7, respectively, can be usedto set the VV interval.

In step 646, the first atrial chamber is sensed or paced, followed bythe second atrium paced at the current AA interval. Following the atrialevents, the first ventricle is paced according to the AV intervalsetting, followed by the second ventricle being paced according to theVV interval setting when biventricular pacing is enabled. Step 646 thususes the AV and VV intervals selected at step 644 and an initial AAinterval selected at step 642.

In step 648, the impedance can be measured at multiple times during theatrial cycle. In one method, the impedance is measured at one or moretimes shortly before, during or after the first atrial event, in orderto catch the atrial cycle minimum impedance, corresponding to pre-atrialejection. The impedance is measured at one or more times after thesecond atrial event until the first ventricular event in order to catchthe atrial cycle maximum impedance, corresponding to atrial emptying. Inanother embodiment of the invention, the impedance is measured atmultiple times after the second A-pace until the next V-event todetermine the maximum impedance. The impedance at or near A-pace can beused in place of the minimum impedance. As previously discussed, whilethe impedance can be measured using pacing signals, separate,sub-threshold signals are used in an exemplary embodiment. Measuringstep 648 can be repeated for the same AA interval for a number ofconsecutive beats in order to obtain an average for the minimum andmaximum impedance values found. An averaged waveform, averaged overseveral cardiac cycles, can also be used to determine the maximum andminimum impedances.

In step 650, the change in impedance, delta Z, over the atrial cycle forthis AA can be determined by taking the difference between the maximumimpedance and the minimum impedance measured during the atrial cycle. Instep 652, the determination is made as to whether the maximum change inimpedance over a range of AA intervals has been found and the searchcomplete. Possible algorithms used to make this determination arediscussed previously. If the AA interval causing the maximum delta Z hasnot been found, then the search can be continued by changing the AAinterval at step 654, and proceeding to step 646. The AA interval may bechanged based on the recent history of impedances obtained for other AAintervals. This process can continue until decision step 652 makes thedetermination that the maximum delta Z has been found, or the algorithmtimes out.

When the maximum delta Z has been found, step 656 can be executed. Instep 656, the AA interval can be set to the AA interval corresponding tothe maximum delta Z. In some embodiments, the AV and VV intervals can bere-optimized using methods described previously herein.

Thus, in methods 620 (FIG. 17) and 640 (FIG. 18), the AA interval isoptimized based on maximizing atrial ejection according to a maximumimpedance or maximum impedance change, respectively, measured during theatrial cycle. In method 600 shown in FIG. 16, the AA interval isoptimized based on maximizing the ejection of blood from the heartmeasured by a maximum impedance change over the entire cardiac cycle.Depending on the type of device being used, the optimization methodsdescribed herein for optimizing the various pacing intervals, includingAA intervals, AV intervals, and VV intervals, may be performed in anycombination, with re-optimization of any interval after optimizinganother interval.

FIG. 19 is a flow chart illustrating an embodiment 700 implemented in anexternal programming device for providing impedance data to any of thepacing interval optimization methods described previously. Method 700 isone example of a method for providing impedance data obtained under anumber of predetermined measurement conditions. For example, pacinginterval optimization methods may be performed under different posturesor heart rates in order to determine the optimal pacing intervals to beapplied during these varying physiologic conditions.

In step 702, method 700 is initiated by a physician by entering acommand on an external programming unit. In step 704, the programmingunit generates a message on a display prompting the physician to directthe patient to perform certain steps so as to achieve the first of oneor more impedance measurement conditions. For example, the patient maybe asked to initially lay supine and perform a breath hold. The treatingphysician can wait for the patient to be appropriately disposed thensend a “go” signal, recognized by the programmer at decision step 706.Once the “go” signal is received by the programming unit, theprogramming unit communicates with the implanted device via a telemetrylink, to enable impedance measurements to proceed. In alternativeembodiments, the “go” signal may be generated internally by theimplanted device upon sensing the requisite conditions, which mayinclude any combination of heart rate, respiration rate (breath hold),activity level, and posture.

In step 708, the implanted device can automatically adjust pacingparameters as needed to carry out the interval optimization methodspreviously discussed to measure the impedance changes over one or moreheartbeats. In one method, the impedance is measured over a single beat.With the impedance measured over one beat, decision step 710 isexecuted, checking for the existence of a stop condition. If the stopcondition is not found, step 708 is repeated, to gather data fromanother heartbeat or beats. In some embodiments, the stop condition atstep 710 consists simply of a timer or heartbeat counter which gathersdata over a certain time interval of heartbeats or number of heartbeats.In another embodiment, a change in the patient condition inconsistentwith the required measurement condition, such as a change patientposture or activity level as determined by an accelerometer and/or alarge change in impedance indicating breathing, may be used to initiatethe stop condition at step 710. In yet another embodiment, the physicianmay manually enter a stop condition using the programming unit if he/sheobserves non-compliance by the patient or finds the measurementcondition medically inappropriate.

After one or more beats has been measured for impedance at step 708, ora stop condition has been met, a determination is made by theprogramming unit at step 712 if all measurement conditions have beenapplied. The measurement conditions may be a predefined set of uniquemeasurement conditions stored in the programming unit or entered by thephysician. If all measurement conditions have not yet been applied, theprogramming unit may proceed to step 704 to generate a prompt indicatingto the physician the next set of instructions to be given to thepatient. For example, the patient may be directed to change posture,achieve and maintain a certain heart rate or activity level or othercondition. The physician may cancel remaining measurement conditions atany time as medically appropriate.

After the data gathering is stopped at step 710 and all measurementconditions have been applied, as determined at step 712, the set ofimpedance data for each of the applied measurement conditions isprovided to a pacing interval optimization method for determining anoptimal interval. The algorithm for selecting the optimal intervalaccording to the impedance measurements may be stored and executed inthe programming unit. In alternative embodiments, the algorithmutilizing the impedance measurement data may be stored and executed inthe implanted device after receiving the impedance measurements from theprogramming unit, with the optimization result being transmitted back tothe programming unit.

In step 716, the result of the optimization algorithm may be reported bythe programming unit through a display or printed report and recommendedas the programmed setting for the particular AA, AV or VV interval beingoptimized. In another embodiment, the programming unit may automaticallyprogram the respective interval according to the optimization algorithmresult through telemetric communication with the IMD, or upon receivinga confirmation command entered by the physician proceed withautomatically programming the optimal interval setting.

The impedance data gathering method 700 shown in FIG. 19 may operate soas to collect impedance data for optimization of one or more pacingintervals according to the type of implanted device and pacing modeselected. For example, for each measurement condition, the implanteddevice may perform multiple impedance measurements for use inidentifying an optimal AA, AV, and/or VV interval by appropriatelysetting pacing intervals in accordance with the optimization methodsdescribed herein before prompting the physician to direct the patient inestablishing the next measurement condition.

FIG. 20 is a flow chart illustrating an embodiment 740 implemented in animplantable medical device for providing impedance data to the pacinginterval optimization methods described previously. In step 742, thepacing interval optimization method is initiated. The initiation stepmay be performed by a physician using an external programming unit ormay be performed by the implanted device in accordance with scheduledperiodic optimizations or upon detection of predefined triggeringcondition, for example a change in a physiological signal sensed by theimplanted device indicating re-optimization may be necessary.

After initiating the pacing interval optimization procedure, theimplanted device waits until a measurement condition is detected at step744. As described above, it may be desirable to collect impedancemeasurements during one or more predetermined measurement conditions inorder to set optimal pacing intervals during varying conditions such asdifferent heart rate levels or posture. At step 744, the implanteddevice may detect a measurement condition based on sensing a heart rate,posture, activity level, respiration or other signal or combination ofsignals. A measurement condition detected by the implanted device mayinclude detecting a point in the respiration cycle to allowrespiration-gated impedance measurements to be performed.

Once a measurement condition is detected at step 744, the implanteddevice performs impedance measurements at step 746 during which pacingintervals are appropriately adjusted according to the pacing intervaloptimization methods described above. Depending on the type of implanteddevice and the programmed pacing mode, impedance measurements may beperformed to provide impedance data to AA, AV, and/or VV intervaloptimization algorithms. Impedance measurements continue until a stopcondition is reached at step 748 as described previously.

If additional impedance measurements are to be acquired under othermeasurement conditions, as determined at decision step 750, method 740returns to step 744 to await detection of a remaining measurementcondition. Once impedance measurements have been performed at allpredefined measurement conditions, or the algorithm times out, themeasured impedance data is provided to the appropriate optimizationalgorithm(s) for determining the optimal pacing interval(s) according toany of the methods described above for determining an optimal AA, AV,and/or VV interval. The respective pacing interval(s) may then beautomatically set to the optimal interval(s) by the implanted device atstep 754. One or more of the AA, AV and VV intervals may each be set toan optimal interval measured at conditions matching the current patientconditions. As the patient condition changes, for example as heart rate,posture and/or activity level changes, one or more of the AA, AV and VVintervals may be adjusted to a different optimal setting measured atconditions matching the new patient condition. In another embodiment,the optimal interval may be found for the current patient condition andwhen the patient condition changes, a new optimal interval may be found.

The present invention explicitly includes within its scope implantablecardiac devices executing programs or logic implementing methodsaccording to the present invention. The present invention's scope alsoincludes computer programs or logic capable of being executed, directlyor indirectly, on implantable cardiac devices. Computer readable mediahaving instructions for implementing or executing methods according tothe present invention are also within the scope of the presentinvention. Embodiments for producing impedance measurements compensatedfor breathing impedance or breathing impedance changes are explicitlywithin the scope of the invention as separate and independent methods,apart from their use in setting AV and VV intervals. Respiratoryimpedance compensating methods, devices implementing those methods,computer programs implementing those methods, and computer readablemedia containing programs implementing those methods are also within thescope of the invention.

The detailed description of the preferred embodiments provided hereinyield a reliable and specific device and methods for automaticdetermination of optimal AV and VV intervals. Numerous variations of thedescribed embodiments are possible for practicing the invention.Therefore, the embodiments described herein should be consideredexemplary, rather than limiting, with regard to the following claims.

1. A method for setting a pacing interval, the method comprising:adjusting the pacing interval to a plurality of settings; measuring animpedance signal sensitive to changes in cardiac volume; determining thepacing interval setting associated with a maximum impedance measurement;and setting the pacing interval to the pacing interval settingassociated with the maximum impedance measurement.
 2. The method as inclaim 1, wherein the pacing interval is an atrial-to-atrial (AA)interval.
 3. The method as in claim 1, wherein the impedance measuringoccurs during the atrial cycle.
 4. The method as in claim 3, wherein theimpedance measuring includes selecting impedance measuring electrodesfor measuring an impedance signal sensitive to changes in atrial volume.5. The method as in claim 1, wherein the maximum impedance measurementis a measurement of a maximum change in impedance.
 6. The method as inclaim 1, wherein adjusting the pacing interval settings includesselecting a plurality of pacing interval settings that converge on themaximum impedance measurement in decreasing time intervals.
 7. Themethod as in claim 6, wherein the selecting pacing interval settings isperformed according to a binary searching method for converging on themaximum impedance measurement.
 8. The method as in claim 1, wherein themeasuring the impedance signal includes measuring the impedance signalat a plurality of time points beginning near an A-pace event until neara next V-event.
 9. The method as in claim 1, wherein the measuring theimpedance signal includes measuring the impedance signal at a pluralityof time points beginning near a V-event until near a next A-event. 10.The method as in claim 1, wherein the measuring the impedance signalfurther includes: sensing a respiration signal; measuring the impedancesignal at a time point corresponding to substantially unchangedimpedance due to respiration.
 11. The method as in claim 10, wherein thesensing includes sensing respiration movement using an accelerometer.12. The method as in claim 10, wherein the sensing includes selecting aset of impedance measuring electrodes for measuring an impedance signalsensitive to respiration.
 13. A system, comprising: at least one pair ofimpedance sensing electrodes; an impedance measurement unit formeasuring the impedance between the electrode pair; a control unit forsetting a pacing interval to a plurality of settings and for causing theimpedance measurement unit to perform an impedance measurement during atleast one cardiac cycle for each of the plurality of pacing intervalsettings; and a processing unit for receiving the impedance measurementsand for determining the pacing interval setting associated with amaximum impedance measurement.
 14. The system according to claim 13wherein the control unit receives from the processing unit the pacinginterval setting during which the maximum impedance was measured and thecontrol unit sets the pacing interval substantially equal to the pacinginterval setting.
 15. The system according to claim 13 wherein theimpedance sensing electrodes are adapted for implantation in a patient'sbody and the impedance measurement unit is included in an implantablemedical device.
 16. The system according to claim 13 wherein the controlunit and the processing unit are included in an implantable medicaldevice.
 17. The system according to claim 13 wherein at least one of thecontrol unit and the processing unit are included in an externalprogramming unit.
 18. The system according to claim 13 further includingan external programming unit including a display unit for displayinginstructions to a physician for directing a patient to perform stepsthat cause the patient to achieve a predetermined physiologicalcondition.
 19. The system according to claim 13 further including aphysiological sensor for detecting a physiological condition and whereinthe control unit causes the impedance measuring unit to performimpedance measurements when the physiological sensor detects apredetermined physiological condition.
 20. The system according to claim19 wherein the predetermined physiological condition is any combinationof the physiological conditions selected from the group of: a heart ratecondition, a respiration condition, a posture condition, and a physicalactivity condition.
 21. A system, comprising: means for varying a pacinginterval setting; means for measuring an impedance signal sensitive tochanges in cardiac volume during at least one cardiac cycle for eachpacing interval setting; means for determining the pacing intervalsetting associated with a maximum impedance measurement; means forsetting the pacing interval to the determined pacing interval settingassociated with the maximum impedance measurement.
 22. A computerreadable medium containing instructions that when implemented in amedical device, cause the device to: adjust a pacing interval to aplurality of pacing interval settings; measure an impedance signal atleast one time point during at least one cardiac cycle for each of thepacing interval settings; and determine the pacing interval settingassociated with a maximum impedance measurement.
 23. The computerreadable medium of claim 22, further causing the device to set thepacing interval to the pacing interval setting associated with themaximum impedance measurement.
 24. The computer readable medium of claim22 wherein the maximum impedance measurement is a maximum change inimpedance.
 25. The computer readable medium of claim 22 wherein thepacing interval is an atrial-to-atrial (AA) interval.
 26. The computerreadable medium of claim 22 wherein the impedance signal issubstantially sensitive to changes in atrial volume.